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NTHL1, MSH3, AXIN2, GREM1 and RNF43: what these genes do | CION Cancer Clinics
NTHL1, MSH3, AXIN2, GREM1 and RNF43 are five rare genes that help keep the lining of the bowel in order. A fault in one of them can cause many polyps to grow, and some polyps can turn into cancer if they are left. This page explains what each gene normally does, how a fault leads to polyps, and why the evidence on all five is still thin. At CION Cancer Clinics, our oncologists explain what a gene result means for you and your family, and plan the checks that follow.
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Medically reviewed by Dr. Naresh GunduConsultant Medical Oncologist · MBBS, DNB (Internal Medicine), DM (Medical Oncology, AIIMS) · last reviewed September 2026, next review due September 2027
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On this page
- What do these five rarer polyposis genes actually do?
- What does each of the five genes normally do?
- How can one faulty gene lead to many polyps?
- Which words will you meet on the report, and what do they mean?
- One faulty copy or two: how do these genes pass down a family?
- What this page cannot tell you
- Four things families tell us, and what is actually true
- Common questions about the rarer polyposis genes
The short answer
What do these five rarer polyposis genes actually do?
Each of these five genes helps keep the lining of the bowel healthy. Two of them repair copying mistakes in DNA. Two act as brakes on a growth signal. The fifth is normally kept switched off in the bowel lining. When one of them is faulty from birth, the lining can grow many polyps, which are small growths that sometimes turn into cancer over years.
Why they are grouped on one page
They are grouped because each one is rare, and each explains only a handful of families worldwide. Most people with many bowel polyps have a fault in a better-known gene called APC or MUTYH, or no gene fault at all. These five are usually looked at when those tests come back normal and the polyps still need an explanation.
Why a laboratory tests them at all
Many bowel cancer and polyp panels now include some or all of them. A result can explain why one person grew so many polyps. It can also tell relatives whether they need earlier colonoscopy. When nothing is found, the family is still watched using the history and the polyp count.
A fault in one of these genes is a statement about risk. It is not a cancer diagnosis.Gene by gene
What does each of the five genes normally do?
The five genes do quite different jobs. That is why they behave differently in families.
NTHL1
A repair gene. It finds one kind of chemical damage in DNA and removes it before the cell copies it. Trouble usually starts only when both copies are faulty. Small studies suggest people with two faults may also have raised risks of some cancers outside the bowel, such as breast and womb.
MSH3
Another repair gene. It belongs to the team that checks each newly copied stretch of DNA for spelling mistakes. It is a cousin of the Lynch syndrome genes and behaves differently from them. Polyps have been linked mainly to people carrying two faulty copies.
AXIN2 and RNF43
Both act as brakes on a growth signal that tells bowel lining cells to divide. One faulty copy can be enough.
Clues seen in families
- AXIN2: several adult teeth that never grew
- RNF43: serrated polyps, a flatter type of growth
GREM1
Here the gene itself is usually intact. An extra copy of a nearby stretch of DNA switches GREM1 on in the bowel lining, where it is normally quiet. This causes a mix of polyp types. It has been found mostly in families of Ashkenazi Jewish ancestry.
Not sure whether this applies to you?
Ask an oncologistFrom fault to polyp
How can one faulty gene lead to many polyps?
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The bowel lining renews itself constantly
The cells lining the bowel are replaced very quickly throughout life. That means constant copying of DNA, and constant chances for small mistakes.
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Repair genes and brakes keep it orderly
Repair genes fix mistakes before they stick. Brake genes stop a cell from dividing when it has no reason to. Together they keep the lining flat and even.
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A fault weakens one of those safeguards
With a repair gene broken, mistakes pile up faster than usual. With a brake weakened, a cell divides more easily than it should. Either way, small clusters of cells begin to grow where they should not.
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Polyps appear, often many of them
Those clusters show up as polyps on the bowel wall. A person with one of these faults may have tens of them, usually found at colonoscopy rather than felt. Most stay harmless for years.
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A polyp left alone can slowly become cancer
Over many years, a small share of polyps can turn into cancer. Removing polyps at colonoscopy breaks that chain, which is why regular checks matter so much for carriers.
On your report
Which words will you meet on the report, and what do they mean?
- Polyp
- A small growth on the inner wall of the bowel. Most are harmless, and most can be removed during a colonoscopy.
- Adenoma
- A type of polyp that can, over years, turn into cancer. It is the kind most often linked to inherited polyp conditions.
- Serrated polyp
- A flatter polyp with a saw-toothed look under the microscope. Some types can also turn into cancer and are harder to spot.
- Polyposis
- Having many polyps rather than one or two. Your specialist decides what count qualifies.
- Biallelic
- Both copies of a gene are faulty, one from each parent. NTHL1 and MSH3 usually cause polyps only in this situation.
- Germline
- Present in every cell from birth, and so it can be passed on. A fault found only inside a tumour is called somatic.
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Side by side
One faulty copy or two: how do these genes pass down a family?
NTHL1 and MSH3: two copies needed
AXIN2, RNF43 and GREM1: one copy enough
Both parents usually carry one silent fault each
Usually one parent carries the fault
Each brother or sister has a one-in-four chance of carrying two faults
Each child has a one-in-two chance of inheriting it
One faulty copy is not known to raise risk much
One faulty copy is what carries the risk
More likely when parents are related by blood
Marriage within the family changes little
Being straight with you
What this page cannot tell you
It cannot tell you what your own result means. The same gene name can carry very different weight depending on the exact variant, whether one or both copies are affected, and how the laboratory classified it. What your specific variant means is a question for the counsellor who ordered the test.
The evidence is thin
These five genes were linked to polyps fairly recently, and each has been studied in few families. Studies so far are small, and almost none come from India. Risk estimates may change as more families are found. Your counsellor will tell you how firm the link is for your gene.
Who this does not apply to
Most people who have one or two polyps removed at a routine colonoscopy do not need this testing. Most families with bowel cancer do not carry a fault in any of these genes. This page is for families where many polyps were found and the usual genes explained nothing.
If your report came from tumour tissue and mentions RNF43, that is a question about the cancer itself. It is covered under targeted therapy.Commonly believed
Four things families tell us, and what is actually true
"Polyps are just polyps. Everybody gets them."
Having one or two in later life is common. Having many, or having them young, is not, and it is a reason to ask about genes. The count and the type both matter.
"Both my parents are healthy, so it cannot be inherited."
With NTHL1 and MSH3, parents usually each carry one silent copy and stay well. The condition shows only in a child who inherits both. Healthy parents are the usual picture here.
"A normal APC test means my polyps are not genetic."
APC is the most common cause, not the only one. MUTYH and the rarer genes on this page explain some families where APC was normal. Many families still find no gene, and they are watched just as carefully.
"Once the polyps are removed, the problem is solved."
Removing polyps lowers the risk from those particular growths. The gene fault stays, and new polyps can grow. That is why carriers need regular colonoscopy for life, on a schedule set by their specialist.
Questions we are asked
Common questions about the rarer polyposis genes
Are these genes the same as Lynch syndrome?
No. Lynch syndrome comes from faults in a small group of mismatch repair genes and usually causes cancer without many polyps. MSH3 is a relative of those genes but behaves differently, and the other four are unrelated. Your counsellor will make clear which condition, if any, applies to you.
Why were these genes tested when my doctor suspected FAP?
Most polyp panels now include rarer genes alongside APC and MUTYH. Testing them together in one sample saves a second test later. If the result shows a fault in one of the rarer genes, it may explain polyps that APC testing could not.
Does carrying one NTHL1 or MSH3 fault put me at risk?
On current evidence, carrying one faulty copy of either gene does not appear to raise bowel cancer risk much. It does matter for your children if your partner carries a fault in the same gene. Your counsellor will say whether your partner should be tested.
Can a normal gene test miss GREM1?
Yes. The GREM1 change is usually an extra stretch of DNA near the gene, not a spelling mistake inside it. Ordinary sequencing can miss this. Ask the laboratory whether its test looks for extra or missing copies of DNA, and whether GREM1 is included.
What do missing teeth have to do with bowel polyps?
AXIN2 helps control how teeth form as well as how the bowel lining grows. Some families with an AXIN2 fault have several adult teeth that never came through, along with bowel polyps. A dentist noticing this pattern is sometimes the first clue.
Does marrying within the family matter here?
For NTHL1 and MSH3 it can. Relatives are more likely to carry the same silent fault, so their child is more likely to inherit two. Such marriages are common in parts of Telangana and South India. Mention it to your counsellor without embarrassment.
Can the faulty gene be repaired?
No. A gene fault cannot be corrected or reversed. What helps is finding polyps early and removing them at colonoscopy, before they have a chance to turn into cancer. Some people with very many polyps are advised surgery, which is a separate discussion with a surgeon.
Where do I start if many polyps were found?
Ask for the colonoscopy and polyp reports, including the type and number of polyps. Take them, with a list of relatives who had bowel cancer, to a genetic counsellor or your oncologist. Call the CION helpline if you are unsure who to approach.
Your Specialists
Meet CION's oncologists. Bring your family history or genetic report to them.
Our medical oncologists see people with a strong family history of cancer, arrange genetic counselling and testing where it fits, and plan the checks that follow.
Medical Oncologist
Dr. C. Raghavendra Reddy
MBBS(Gold Medal), DNB(General Medicine), DM(Medical Oncology)(Gold Medal)
Medical Oncologist
Dr. Bharati Devi Gorantla
MBBS, MD(General Medicine), DM(Medical Oncology)(Adyar,Chennai), ECMO, MRCP SCE(UK)
Medical Oncologist
Dr. Owais Mohammed
MBBS, MD (General Medicine), DrNB (Medical Oncology), ECMO, MRCP SCE (Medical Oncology) (UK)
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Sources
- National Cancer Institute — Genetics of Colorectal Cancer (PDQ®)–Health Professional Version
- NCCN — Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric
- MedlinePlus Genetics — AXIN2 gene
- MedlinePlus Genetics — What are the different ways a genetic condition can be inherited?
This page is general information, not a prescription. Do not change or stop any treatment based on what you read here. If anything is worrying you, contact your own treating team — or call our helpline and we will help you reach the right specialist.
Keep reading
Related pages
Rarer polyposis genes: which cancers and what riskWhich cancers these genes raise, and how firm the evidence isTesting the family for the rarer polyposis genesWho in the family should be tested nextSerrated polyposis syndrome and its geneticsWhere RNF43 fits, and why most families find no geneThe MUTYH geneThe better-known repair gene these are compared with
Talk to us
Many polyps and no answer from the usual genes?
Tell us how many polyps were found and who in the family had bowel cancer. We will help you work out whether a wider gene test makes sense. One helpline serves every CION centre.